20-41202162-T-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001384317.1(ZHX3):āc.2755A>Gā(p.Thr919Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Consequence
NM_001384317.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ZHX3 | NM_001384317.1 | c.2755A>G | p.Thr919Ala | missense_variant | Exon 3 of 4 | ENST00000683867.1 | NP_001371246.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152094Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000163 AC: 41AN: 251358Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135834
GnomAD4 exome AF: 0.0000814 AC: 119AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.0000715 AC XY: 52AN XY: 727244
GnomAD4 genome AF: 0.000112 AC: 17AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74410
ClinVar
Submissions by phenotype
not provided Uncertain:1
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 919 of the ZHX3 protein (p.Thr919Ala). This variant is present in population databases (rs748783597, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ZHX3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1402056). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at